Pyridone derivatives

ABSTRACT

The present invention deals with 2,6-dimethyl-1,4-dihydro-4-oxo3,5-pyridine-dicarboxylates and derivatives, a manner for their preparation and their utility as anti-inflammatory agents. The said 4-oxo pyridines of the present invention commonly referred to the chemical literature as 4-(1H)-pyridones are suitably prepared by reacting a 2,6-dimethyl-4-oxo-3,5-pyronedicarboxylate with an aniline in an acetic medium such as acetic acid.

United States Patent [191 Haberet al.

[ PYRIDONE DERIVATIVES [75] Inventors: Raphael Ralph G. Haber,

Givatayim; Chaim Simonovitch, Rishon Letzion, both of Israel [73] Assignee: Abic Ltd., Ramat-Gan, Israel OTHER PUBLlCATlONS Ettel et al., Chem. Abstracts, Vol. 46, No. 1, pages -504g to 506-21. -Hebky, Chem. Abstracts, Vol. 47, No. 7, page June 28, 1974 3310-b-g, April I0, 1953. Hebky et al., Chem. Abstracts, Vol. 47, page H, 187-b-g, October 10, 1953.

Primary Examiner-Alan L. Rotman Attorney, Agent, or FirmSteinberg & Blake [57], ABSTRACT The present invention deals with 2,6-dimethyl-l,4- dihydro-4-oxo-3,5-pyridine-dicarboxylates and derivatives, a manner for their preparation and their utility as anti-inflammatory agents. The said 4-oxo pyridines of the present invention commonly referred to the chemical literature as 4-(lH)-pyridones are suitably prepared by reacting a 2,6-dimethyl-4-oxo-3,5- pyronedicarboxylate with an aniline in an acetic medium such as acetic acid.

34 Claims, N0 Drawings 1 PYRIDONE DERIVATIVES The present invention relates to new antiinflammatory and analgesic compositions.

There are known various anti-inflammatory agents, e.g. certain steroids (cortisone and its derivatives); acetyl salicylic acid (hereinafter called aspirin), butazolidin or indometacin. However, most of these known agents have unpleasant side effects, e.g. they cause ulcers.

It has thus been desirable to find compounds, which are useful anti-inflammatory agents, which are substantially as effective as the known antiinflammatory agents but which have less unpleasant side effects.

M. Conrad and M. Guthzeit (Ber.,19( I886) and Ber.,20, 154 (l887) describe the preparation of 2,6- dimethyl-3,5-dicarboethoxy-4-pyridone, 2,6-dimethyl- 3,5-dicarboethoxy-N-phenyl-4-pyridone, 2,6-dimethyl- 3,5-dicarboethoxy-N-methyl-4-pyridone and 2,6- dimethyl-3,5-dicarboethoxy-N-acetyl-4-pyridone.

V. Ettel and J. Hebky, Coll. Czech.Chem.Com., 15, 639 1950) and J. Hebky, Coll. Czech.Chem.Com., 16, 348 l95l describe the synthesis of some of the same compounds as well as:

2,6-Dimethyl-3,5-dicarboethoxy-N-(p-hydroxyphenyl)-4-pyridone and its diacid; 2,6-Dimethyl-3,5-dicarboethoxy-l I-(m-hydroxyphenyl)-4-pyridone and its di'acid; 2,6-Dimethyl-3,5-dicarboethoxy-N-(4'-hydroxy- 3,5'-di-methoxy phenyl)-4-pyridone and its diacid; 2.o-dimethyl-3,5-dicarboethoxy-N-(p-acetamidophenyl)-4 -pyridone and its diacid; l,4-bis-N,N 2',6'-dimethyl-3 ',5 '-dicarboethoxy-4- pyridone)-phenylene and its tetracid; v 2,6-dimethyl-3,5-dicarboethoxy-l l-(p-lodophenyl)- 4-pyridone and its diacid; I 2,6-dimethyl-3,5-dicarboethoXy-N-(2,4'-Diiodophenyl)-4-pyridone and its diacid; 2,6-dimethyl-3,5-dicarboxy-N-(4'-hydroxy-3',5'-

diiodophenyl )-4-pyridone 2,6-dimethyl-3,5-dicarboxy-N-( 3 -hydroxy-2',4,6-

triiodophenyl)-4-pyridone. Ettel & Hebky studied these compounds because of their interest in a novel X-Ray contrast agent for a similar use as the known diethanolamine salt of 3,5-diiodo- 4-pyridone-N-acetic acid. They thus prepared and tested salts of the various above mentioned 2,6-dimethyl-N-( various Iodophenyl )-4-pyridone-3 ,5- dicarboxylic acids as X-Ray contrast agents.

We have now surprisingly found that certain esters of 2,6-dirnethyl-N-substituted-4-pyridone-3,5- dicarboxylic acid have good anti-inflammatory properties substantially without having the unpleasant side effects of the known anti-inflammatory agents. Moreover, some of said pyridones have useful analgetic properties and some have beta-blocking properties. The free acids show substantially no activity while if the nitrogen carries no substituent the compounds are new rotoxic.

The present invention thus consists in pharmaceutical compositions comprising as active substance a pyridone derivative of the general formula I in which R, and R stand for the same or different substituted or unsubstituted alkyl, alkylene, cycloalkyl or benzyl radicals and R'stands for a phenyl radical which may be optionally substituted with one or more substituents selected from the group comprising alkyl, alkoxy,

nitro, chloro, fluoro and dialkylamino radicals which may be the same or different.

Pyridones of general formula I comprise also bispyridones of general formula II "mote CH5 cm'e'oo'm 0 N N o mozb on. R; on, 00112 in which R and R have the same meaning as above and R stands for hydrogen or for one or more substituents' selected from the group comprising alkyl, alkoxy, nitro, chloro, fluoro, and substituted amino radicals which may be the same or different.

Many of the compounds of general formula I are new compounds. The present invention thus consists also in pyridone derivatives of general formula I wherein R and R have the same meaning as above and R stands for a phenyl radicalsubstituted with one or more substituents selected from the group comprising alkyl, alkoxy, nitro, chloro, fluoro and dialkylamino radicals which may be the same or different.

The compounds of the present invention may be prepared by various suitable methods. A suitable process consists in reacting apyrone of general formula II] I with an amine of generalformulaIV ethyl (or methyl) may be transesterified by boiling with an excess of the appropriate alcohol in the presence of an acid as catalyst and the lower boiling alcohol (methanol or ethanol) is removed by distillation. By this process only one group is transesterified.

Should both R and R have to be different from ethyl, the carboethoxy groups of the pyridone may be EXAMPLE 2 6.7 g. of o-toluidine were added to a solution of 8.5 g. of the pyrone in 60 ml. of glacial acetic acid. The

subjected to saponification and the compound b- 5 mixture was stirred and heated at 110 for 1 hour. The

tained is esterified with the desired alcohol. Said esterification is preferably performed by first preparing the I acid chloride, e.g. by reacting the 2,6-dimethyl-3,5-

inducedoedema test on the hind paw of rats or in the cotton pellet granuloma test in rats. At present we found the 4-alkoxyphenyl derivatives to be the most active ones.

Significant anti-inflammatory activity and a good dose response was found at dosages between 50 mg/kg 'body weight and 200 mg/ kg when administered orally or intraperitoneally.

Moreover, compounds of the pyridone derivatives of general formula l show a low ulcerogenic index at the effective anti-inflammatory dosage.

Some of the compounds demonstrated analgetic properties estimated by measuring the pain threshold in rats by the method of Randall and Selitto.

The toxicity of the tested compounds was quite low.

The present invention thus consists also in a method for the treatment of inflammations and/or for the relief of pain with a therapeutic dosage of a pyridone derivative of general formula 1 or with a composition containing same.

The invention will now be illustrated with reference to the following Examples without being'restricted by them.

EXAMPLE 1 v 2,6-dimethyl-3,5-dicarboethoxy-N-phenyl-4- pyridone was prepared according to Conrad and Guthzeit (-M. Conrad and M. Guthzeit, Chem. Ber., 19, 19- 26, 1886)), by reacting 2,6-dimethyl-3,5-dicarboe- I thoxy-4-pyrone (said compound will be called hereinafter the pyrone") and aniline in acetic acid. (mp. 170C).

The compound has a good inhibitory effect on the development of Carrageenin induced Oedema in rats at a dose of 50 mg/kg and very good activity at the doses of 100 and 200 mg/kg, via oral or i.p. administration.

mixture was then cooled and poured into '100 g. of crushed ice. The mixture obtained was neutralised with concentrated ammonia to pH 6 and the precipitate was filtered off, washed with water and dried yielding 8 g. of 2,6-dimethyl-3,5-dicarboethoxy-N-(2-methyl phenyl)-4-pyridone; mp. 178C.

The compound has a good inhibitory effect on the development of Carrageenin induced Oedema in rats at doses of 100 mg/kg and very good effects at 200 mg/kg. A very low ulceration index was recorded at a dose of 200 mg/kg in comparison to aspirin and indomethacin.

EXAMPLE 3 precipitate was filtered off by suction, washed with water and dried to yield 3 g. of crude 2,6-dimethyl-3,5-

' dicarboethoxy-N-(3'-chlorophenyl)-4-pyridone; mp.

In doses of mg/kg and 200 mg/kg the compound inhibited the cotton pellet granuloma formation in rats.

'Theactivity was greatly reduced when adrenolectromised rats were used in the experiments. A low ulceration index was recorded at doses between 50 mg/kg to 200 mg/kg in comparison with aspirin and indomethacin.

204-206. After recrystallization from benzene the m.p. was 209-210C.

At a dose of 200 mg/kg the compound exhibited moderate anti-inflammatory effect in the Carrageenin induced oedema.

In the same manner were prepared: 2,6-dimethyl3,5-dicarboethoxy-N-(4-chlorophenyl)-4-pyridone m.p. 129: 2,6-dimethyl-3,5-dicarboethoxy-N-(4-fluorophenyl)-4-pyridone m.p. 169: 2,6-dimethyl-3,5-dicarboethoxy-N-( 2'-fluorophenyl)-4-pyridone m.p. 112: 2,6-dimethyl-3,5-dicarboethoxy-N-(3'-fluorophenyl)-4-pyridone m.p. 212:

EXAMPLE 4 2 g. of pyrone were reacted with 1.5 g. of 4-nbutoxyaniline in the same manner as described in Example 2 to yield 3 g. of 2,6-dimethyl-3,5- dicarboethoxy-N-( 4'-n-butoxyphenyl )-4-pyridone; m'.p. l34-5C.

The compound has a good inhibitory effect on the development of Carrogeenin induced Oedema in rats at a dose of 100 mg/kg and a very good effect at a dose of 200 mg/kg. The compound also inhibited, granuloma formation in intact and adrenalectomized rats at the doses of 100 mg/kg and 200 mg/kg.

A low ulcerogenic index was recorded at the doses described above. At a dose of 200 mg/kg the compound had a good effect on adjuvant arthritis in rats, as compared to indomethacin. A good analgesic activity was observed at a dose of 200 mg/kg as compared to aminopyrine.

The following compounds were prepared injthe same manner:

2,6-dimethyl-3 ,5-dicarboethoxy-N-( 4'-ethoxyphenyl)-4-pyridone; m.p. 2,6-dimethyl-3,5-dicarboethoxy-N-(4' pheny1)-4-pyridone; m.p. l 5916() methoxy- 5 2,6-dimethyl-3,5 dicarboeth'oxy-N-(4-isobuthoxyphenyl)4-pyridone; m.p. 110 2,6-dimethyl-3,5-dicarboethxy-N-(4'-isopentyloxyphenyl)4-pyridone; m.p. 168 2,6-dimethyl-3,5-dicarboethoxy-N-(4-heptyloxyphenyl)4-pyridone; m.p. 102 2,6-dimethyl-3,5-dicarboethoxy-N-(4-octyloxyphenyl)4-pyridone; m.p. 86 2,6-dimethyl-3,5-dicarboethoxy-N-(4- tetradecyloxyphenyl)-4-pyridone; m.p. 87 2,6-dimethyl-3,S-dicarboethoxy-N-(4-octadecyloxyphenyl)4-pyridone; m.p. 90 2,6-dimethyl-3,5-dicarboethoxy-N-(4'-decyloxyphenyl)4-pyridone; m.p. 87 2,6-dimethyl-3,5-dicarboethoxy-N-(4 cyclohexyloxyphenyl)4-pyridone; m.p. 170 2,6-dimethyl-3,5-dicarboethoxy-N-(4- heptadecyloxyphenyl)4-pyridone; m.p. 85 2,6-dimethyl-3,5-dicarboethoxy-N-(4-pentyloxyphenyl)4-pyridone; m.p. 92 2,6-dimethyl-3,5-dicarboethoxy-N-(4'(3"hexyloxy)- phenyl)4-pyridone; m.p. 145 2,6-dimethyl-3,5-dicarboethoxy-N-(4- pentadecyloxyphenyl)4-pyridone; m.p. 95

2,6-dimethyl-3,5-dicarboethoxy-N-(4(4"heptyloxy)phenyl)4-pyridone; m.p. 116 2 ,6-dimethyl-3 ,5-dicarboethoxy-N-(4'( 2 heptyloxy)phenyl)4-pyridone; m.p. 90 g I 2,6-dimethyl-3,5-dicarboethoxy-N-(4(4"octyloxy)- phenyl)4-pyridone; m.p. 104 2,6-dimethyl-3,5-dicarb0ethoxy-N-(4(3"pentyloxy)phenyl)4-pyridone; m.p. 172 v 2,6-dimethyl-3,5-dicarboethoxy-N-(4'propoxyphenyl)4-pyridone; m.p.' 122 2,6-dimethyl-3,5-dicarboethoxy-N-(4hexyloxyphenyl)4-pyridone; m.p. 104 2,6-dimethyl-3,5-dicarboethoxy-N-(24'-dimethoxy)4-pyridone; m.p. 178 1n the Carrogeenin induced Oedema in the rat the compounds described above showed good to very good activity at a dose of 200 mg/kg and some have moderate to good angesic activity at the same dose.

EXAMPLE 5 EXAMPLE 6 1.25 g. of the pyrone was reacted with 2.3 g. of dimethyl aniline in the same manner as described in Example 2 to yield 1.7 g. of 2,6-dimethyl-3,5-dicarboethoxy-N-(2,

3'-dimethyl-phenyl)-4-pyridone; m.p. 110 (recrystallised from benzene petrol-ether 40-60C) At a dose of 200 mg/kg the compound showed moderate anti-inflammatory effect on the Carrageenin induced oedema in rats.

EXAMPLE 7 2 g. of the pyrone and 1.1 g. of 4-nitroaniline were dissolved in ml. of acetic acid and the mixture was stirred and heated to 1 10 for 24 hours. Thereafter the 6 mixture was cooled and poured into g. of crushed ice. The suspension was neutralised to pH 7 with concentrated ammonia and the crystals obtained were filtered off and dried.

Yield: 1.5 g. of 2,6-dimethyl-3,5-dicarboethoxy-N- (4-nitropheny1)-4-pyridone; m.p. 195.

At a dose of 200 mg/kg the compound showed good anti-inflammatory effect on the Carrageenin induced oedema in rats.

EXAMPLE 8 At a dose of 200 mg/ kg the compound showed" weak anti-inflammatory effect on the Carrageenin induced oedema in rats.

EXAMPLE 9 2 g. of the pyrone were reacted with 1.32 g. of 4- diethyl amino aniline in the same manner as described in Example 8 to yield 2,6-dimethyl-3,S-dicarboethoxy- N-( 4'-diethylaminophenyl )-4-pyrid0ne; m.p. 138.

At a dose of 200 mg/kg the compound showed good anti-inflammatory effect on the Carrageenin induced oedema in rats.

EXAMPLE l0 4 g. of 2,6-dimethyl-3,5-dicarboethoxy-N-phenyl-4- pyridone (prepared as described in Example 1) were dissolved in 20 ml. of benzyl alcohol, 4 drops of concentrated H SO were added and the mixture was stirred and heated for 7 hours at at the same time distilling off the produce ethanol. The benzyl alcohol solution was washed with a saturated solution of sodium bicarbonate and the slurry was extracted several times with chloroform. The extracts were combined and dried over magnesium sulphate, and the chlorofonn was distilled off in vacuo. The oily residue waw dissolved in 50 ml. of ether and 50 m1. of petrol-ether 40-60 were added. After cooling in a dry ice-acetone bath and scratching, 2.5 g. of 2,6-dimethyl-3- carboethoxy-5-carbobenzyloxy-N-phenyl-4-pyridone, m.p. 142 were obtained.

At a dose of 200mg/kg the compound showed weak anti-inflammatory effect on the Carrageenin induced oedema in rats.

EXAMPLE 1 l 1.5 g. of 2,3-dimethyl-3,5-dicarboethoxy-N-phenyl- 4-pyridone (prepared as described in Example 1) was dissolved in 45 m1. of butanol, 2 drops of concentrated sulfuric acid were added and the mixture was stirred and heated at 100 for seven hours, and the produced ethanol was distilled off simultaneously. The mixture was cooled, transferred into a separatory funnel and shaked with a saturated solution of sodium bicarbonate. The organic phase was separated and evaporated to dryness. The residue was crystallised from isopropa- At a dose of 200 mg/kg the compound showed mod-- erate anti-inflammatory activity on the Carrageenin induced oedema in rats.

EXAMPLE 2 The tetra ethyl ester of phenylene-1,4-bis-N,N'-(2,6- dimethyl-3,S-dicarboxylic acid-4-pyridone) was prepared according to Ettel (V. Ettel and J. Hebky, Coll. Czech. Chem. Commun., 15, 639-651 (1950)) by reacting p-phenylene diamine with the pyrone in acetic acid.

The compound has a good inhibitory effect on the development of Carrageenin induced Oedema in rats at a dose of 100 mg/kg and very good effect at a dose of 200 mg/kg. The compound inhibited granuloma formation in intact and adrenalectomised rats at doses of 100 mg/kg and 200 mg/kg. Low ulcerogenic indexes was recorded at the doses described above as compared to indomethacin. A very good analgesic activity was observed at a dose of 200 mg/kg as compared to amino pyrine.

EXAMPLE l3 2,6-dimethyl-N-phenyl-4-pyridone-3,5-dicarboxylic acid was prepared according to Conrad and Guthzeit (M. Conrad and M. Guthzeit, Chem. Ber., 20, 154-163 1887)).

A solution of l g. of the diacid and 1,23 g. of thionyl chloride in 50 m1. of benzene was refluxed for four hours. The solvent was removed in vacuo. To the residue were added 50 ml. of anhydrous methanol and the mixture was refluxed for 1 hour. The methanol was removed in vacuo', water was added and the acid solution was neutralised to pH 6.5. The material which had been precipitated was filtered off and dried in the air to yield 2.6-dimethyl-3,5-dicarbomethoxy-N-phenyl-4- pyridone; 88.5 percent yield; m.p. 215.

EXAMPLE 14 A solution of l g 2,6-dimethyl-3,5-carboxy-N-pheny1-4-pyridone and 1.23 g. of thionyl chloride in 50 ml of benzenewas refluxed for four hours. The solvent was removed in vacuo. To the residue were added 50 ml. of

isopropyl alcohol and the mixture was refluxed for 1 hour. The solvent was removed in vacuo, water was c. 2,6-dimethyl-3,5-dicarbo isobutyloxy-N-phenyl-4- pyridone; mp 200C (1. 2,6-dimethyl-3,5-dicarbo butyloxy-N-phenyl-4- pyridone.

EXAMPLE 15 Tablets of a pyridone can be prepared in the following manner:

Blend together 400 g of 2,6-dimethyl-3,5-

dicarboethoxyN-(4-heptyloxy phenyl)-4-pyridone- (active compound) and g lactose with starch paste (made of 25 g starch) dry in the oven at 45C overnight. Pass the dry granulation through a No. 16 stainless steel screen. To the screened granulation add 2.7 g stearic acid and 50 g talcum (previously screened through a size 40 stainless steel screen) and compress to tablets.

In this way each tablet contains:

Active compound 400 mg Lactose 100 mg Starch 25 mg Stearic acid 2.7 mg Talcum 50 mg EXAMPLE 16 Capsules of a pyridone can be prepared in the following manner:

Blend well 400 g of 2,6-dimethyl-3,5-dicarboethoxy- N-(4'-hepty1oxyphenyl)-4-pyridone (Active compound) and 200 g lactose and 60 g of Cabosil and fill into capsules. Each capsule contains:

Active compound 400 mg Lactose 200 mg Cabosil (Fumed silica of Cabot Corp.) 6 mg EXAMPLE 17 Active compound 400 mg Starch 200 mg Mg stcurate 1.5 mg

Example 18 Suppositories of a pyridone can be prepared as follows:

Melt at 50C 16 g of cocoa butter, add 40 mg of 2,6- dimethyl-2,5-dicarboethoxy-N-(4-n-buthoxy phenyl)- 4-'pyridone, homogenize if necessary, pour into moulds and allow to congeal. Extrude suppositories and wrap.

' EXAMPLE 19 Active compound 0.471 ccto-stearyl alcohol methyl parabene 0.271 propyl parahcne 0.05% water quantity sufficient to i007:

1 EXAMPLE A suspension of a pyridone may be prepared in the following manner: g

into 50 ml. of boiling water dissolve 200 mg of methyl parabene and 50 mg of propyl parabene and then add with vigorous agitation carbomethylcellulose (CMC) (100 mg), vee gum (5 g)(Vee gum stands for magnesium aluminium silicate of Vanderbilt), sugar (30 g) and 70% solution of Sorbo (20g)( 70% Sorbitol).

Continue agitation until gums are fully hydrated. Dust on the 2,6-dimethyl-3,5-dicarboethoxy-N-(4'-3"- pentyloxy)-4-pyridone)-(active compound) (2 g), mix well and homogenize. v The suspension thus obtained consists of:

Active compound 2// \ee (ium 5'71 CMC (l. l'/ Methyl parubenc 0.2 /1 Propyl ptirahcne 0.5% Sorhitol (7071 solution) 20% Flavoured water sufficient to I00?! We claim: i I. A pyridone derivative of the formula:

wherein R is selected from the group consisting of phenyl, and substituted phenyl substituted with up to two substituents selected from the group consisting of lower alkyl, lower alkoxy or straight chain alkoxy up to 18 carbon atoms, nitro, Cl, F and di-loweralkylamino,

and wherein when R is phenyl substituted with loweralkyl of more than two carbon atoms lower alkoxy or straight chain alkoxy up' to 18 carbon atoms or amino or di-loweralkylamino then R and R are both selected from the group consisting of the same or different loweralkyl, cycloalkyl of up to six carbon atoms and benzyl, and when R is phenyl or phenyl substituted with loweralkyl of up to'two carbon atoms or alkoxy of up to two carbon atoms or C1 or F then R and R are each selected from the group consisting of lower alkyl wherein one alkyl is of more than two carbon atoms when the other substituent is also lower alkyl, cycloalkyl of up to six carbon atoms and benzyl.

2. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4'-n buthoxypheny1)-4-pyridone.

3. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,S-dicarboethoxy-N-(4'-methoxyphenyl)-4-pyridone,

8. A pyridone derivative according to claim 1 being I 2,6-dimethyl-3-carboethoxy-5-carbobenzyloxy-N-phenyl-4-pyridone.

9. A pyridone derivative according to claim 1, being 2,6-dimethyl-3-carboethoxy-5-carbobuthoxy-N-phenyl-4-pyridone.

10. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4'-isobuthoxyphenyl)-4-pyridone.

11. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,-5-dicarboethoxy-N-(4'-isopentyloxyphenyl)-4-pyridone.

12. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4-pentyloxyphenyl)-4-pyridone.

13. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4'-heptyloxyphenyl)-4-pyridone.

14. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4-octyloxyphenyl)-4-pyridone.

15. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4-tetradecyloxyphenyl)-4-pyridone.

16. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4'-octadecyloxyphenyl)-4-pyridone.

l7. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4-decyloxyphenyl)-4- pyridone.

18. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4'-cyclohexyloxyphenyl)-4-pyridone.

19. A pyridone derivative according to claim 1 being 2,-6-dimethyl-3,5-dicarboethoxy-N-(4-heptadecyloxyphenyl)-4-pyridone.

20. A pyridone derivative acccording to claim 1 being 2,6-dimethyl-3,S-dicarboethoxy-N-[4'-( 3 hexyloxy )-phenyl ]-4-pyridone.

21. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4-pentadecyloxyphenyl)-4-pyridone.

22. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,S-dicarboethoxy-N-[4-(4"- heptyloxy)-phenyll-4-pyridone.

23. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-[4-(2heptyloxy)- phenyl ]-4-pyridone.

24. A pyridone derivative according to claim 1 being 2.6-dimethyl-3,5-dicarboethoxy-N-[4-(4"-octyloxy)- phenyl ]-4-pyridone.

25. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-[ 4'-( 3 pentyloxy)-phenyl]-4-pyridone.

26. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4propoxyphenyl)- 4-pyridone.

27. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4-hexyloxyphenyl)-4-pyridone.

28. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(2,4-dimethoxy- UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION M .21 I JLEEQE:E..- ,.E114,

InVentor(S) Haber, Raphael Ralph G. and Simonovitch, Chaim It is certified that error appears in the aboveidentified patent and that said Letters Patent are hereby corrected as shown below:

[30] Foreign Application Priority Data pril 14, 1971 Israel..... 36627 Signed and sealed this 10th day of December 1974.

(SEAL) Attest:

McCOY M. GIBSON JR. (3. MARSHALL DANN Attesting Officer Commissioner of Patents FORM PO-105O (10-69) USCOMM-DC GONG-P69 u.s, GOVERNMENT PRINTING omc: I969 o-sss-au. 

2. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4''-n buthoxyphenyl)-4-pyridone.
 3. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4''-methoxyphenyl)-4-pyridone.
 4. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(2'',3''-dimethylphenyl)-4-pyridone.
 5. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4''nitro-phenyl)-4-pyridone.
 6. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4''-dimethylamino-phenyl)-4-pyridone.
 7. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4''-diethylamino-phenyl)-4-pyridone.
 8. A pyridone derivative according to claim 1 being 2,6-dimethyl-3-carboethoxy-5-carbobenzyloxy-N-phenyl-4-pyridone.
 9. A pyridone derivative according to claim 1, being 2,6-dimethyl-3-carboethoxy-5-carbobuthoxy-N-phenyl-4-pyridone.
 10. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4''-isobuthoxyphenyl)-4-pyridone.
 11. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4''-isopentyloxyphenyl)-4-pyridone.
 12. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4''-pentyloxyphenyl)-4-pyridone.
 13. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4''-heptyloxyphenyl)-4-pyridone.
 14. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4''-octyloxyphenyl)-4-pyridone.
 15. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4''-tetradecyloxyphenyl)-4-pyridone.
 16. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4''-octadecyloxyphenyl)-4-pyridone.
 17. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4''-decyloxyphenyl)-4-pyridone.
 18. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4''-cyclohexyloxyphenyl)-4-pyridone.
 19. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4''-heptadecyloxyphenyl)-4-pyridone.
 20. A pyridone derivative acccording to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4''-(3''''-hexyloxy)-phenyl)-4-pyridone.
 21. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4''-pentadecyloxyphenyl)-4-pyridone.
 22. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4''-(4''''-heptyloxy)-phenyl)-4-pyridone.
 23. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4''-(2''''heptyloxy)-phenyl)-4-pyridone.
 24. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-diCarboethoxy-N-(4''-(4''''-octyloxy)-phenyl)-4-pyridone.
 25. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4''-(3''''-pentyloxy)-phenyl)-4-pyridone.
 26. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4''propoxyphenyl)-4-pyridone.
 27. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4''-hexyloxyphenyl)-4-pyridone.
 28. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(2'',4''-dimethoxyphenyl)-4-pyridone.
 29. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboethoxy-N-(4''-ethoxyphenyl)-4-pyridone.
 30. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboisopropyloxy-N-phenyl-4-pyridone.
 31. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarbocyclohexyloxy-N-phenyl-4-pyridone.
 32. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarbo (1''-propene)-yloxy-N-phenyl-4-pyridone.
 33. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarboisobutyloxy-N-phenyl-4-pyridone.
 34. A pyridone derivative according to claim 1 being 2,6-dimethyl-3,5-dicarbobutyloxy-N-phenyl-4-pyridone. 